FDA Updates Warning Labels of ESAs in Cancer Patients

April 1, 2007

The number of mutated genes driving the development of cancer is larger than previously believed, a finding that unveils a new challenge for researchers.

ROCKVILLE, Maryland—FDA has issued a black box warning against using higher than necessary doses of erythropoiesis-stimulating agents (ESAs). The agency ordered several labeling changes after receiving additional safety data from studies showing serious adverse effects related to the use of Aranesp (darbepoetin alfa, Amgen) and Epogen and Procrit (epoetin alfa, Amgen and Ortho Biotech).

The black box warning cautions physicians to use the lowest dose of an ESA needed to gradually increase hemoglobin to the lowest level sufficient to avoid transfusions. FDA emphasized that ESAs are not indicated for cancer patients who are not receiving chemotherapy or radiation therapy, as they increase mortality in these patients when administered to target a hemoglobin level of 12 g/dL. [See ONI February 2007, page 27.]

The agency also reminded physicians that ESAs are approved only to reduce the need for red blood cell transfusions. "These products have not been shown to improve or relieve the symptoms of anemia, or to improve quality of life in patients with cancer," FDA said. The black box warning states that ESAs increased the risk of death and serious cardiovascular events when administered to target a hemoglobin level higher than 12 g/dL.

The warning and other labeling changes flowed from several studies that will be discussed at the May 10 Oncology Drugs Advisory Committee (ODAC) meeting to re-evaluate the safety and dosing of ESAs in cancer patients. Soon after FDA revealed the new labeling, the Centers for Medicare and Medicaid Services ordered a review of all Medicare policies related to the use of ESAs.

In its announcement, FDA briefly described findings from six of the studies that led to the updated warning.

•In DAHANCA 10, a randomized study in 522 patients with advanced head and neck cancer treated with radiation therapy, an interim analysis of 484 patients found a significant 10% increase in the locoregional failure rate among patients treated with darbepoetin, compared with placebo. Patients who received darbepoetin to raise hemoglobin to greater than 12 g/dL had a shorter time to progression, compared with placebo.

•Epoetin was associated with a shortened overall survival rate and an increased death rate attributed to disease progression at 4 months in the randomized BEST study of 939 women with metastatic breast cancer undergoing chemotherapy who received the ESA to maintain a hemoglobin count of 12 to 14 g/dL. Researchers ended the trial prematurely because of higher mortality in the epoetin-treated women vs placebo (8.7% vs 3.4%) and a higher fatal thrombotic event rate (1.1% vs 0.2%). At study termination, 12-month overall survival was lower in the epoetin patients (70% vs 76%).

•A phase III randomized trial of 989 patients with active malignant disease not receiving chemotherapy or radiation therapy found more deaths with darbepoetin to achieve a hemoglobin count of 12 g/dL vs placebo (26% vs 20%) after 16 weeks of treatment. At a median follow-up of 4.3 months, the absolute death rate stood at 49% vs 46%, respectively.

•In a randomized trial of anemic patients with advanced non-small-cell lung cancer not on chemotherapy, an interim analysis in 70 patients found a significant decrease in median survival in the epoetin patients, 68 days vs 131 days for placebo.

•A 681-patient study showed a higher incidence of deep vein thrombosis among spinal surgery patients who received epoetin preoperatively to reduce allogenic red blood cell transfusions (4.7% vs 2.1% for standard care). These patients did not receive prophylactic anticoagulation.

•The randomized CHOIR trial of 1,432 anemic chronic renal failure patients who were not undergoing dialysis found major cardiovascular events in 18% of those taking epoetin to obtain a hemoglobin count of 13.5 g/dL vs 14% in those targeting a level of 11.3 g/dL.